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Updated: Jun 28, 2026
Neurogenesis Using P19 Embryonal Carcinoma Cells
Published on: April 27, 2019
P18 is a tumor suppressor gene involved in human medullary thyroid carcinoma and pheochromocytoma development
Wendy van Veelen1, Rob Klompmaker, Martijn Gloerich
1Division of Biomedical Genetics, Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Utrecht, The Netherlands.
Abstract:
In multiple endocrine neoplasia syndrome Type 2 (MEN2), medullary thyroid carcinoma (MTC) and pheochromocytoma (PC) are associated with hereditary activating germ-line mutations in the RET proto-oncogene. Also in a large percentage of sporadic MTCs and PCs, somatic RET mutations appear to be involved in tumor formation. In one single MEN2 family an extensive variety in disease expression may be observed, indicating that additional genetic events are responsible for progression of the disease towards a more aggressive phenotype. However, these additional mutations in both hereditary and sporadic MTC and PC development are largely unknown. Here, we show for the first time the presence of somatic mutations in the cell cycle regulator P18 in human RET-associated MTCs and PCs. Each of these mutations causes an amino acid substitution in the cyclin dependent kinase-interacting region of P18(INK4C). Since these mutations partly inhibited P18(INK4C) function and reduced its stability, our findings implicate P18 as a tumor suppressor gene involved in human MTC and PC development.
Insights
Somatic mutations in the P18 gene were discovered in medullary thyroid carcinoma (MTC) and pheochromocytoma (PC). These P18 mutations suggest its role as a tumor suppressor in RET-associated cancers.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Multiple Endocrine Neoplasia syndrome Type 2 (MEN2) involves medullary thyroid carcinoma (MTC) and pheochromocytoma (PC), often linked to RET proto-oncogene mutations.
- While RET mutations are established drivers, additional genetic factors influencing disease progression and phenotype variability in MTC and PC remain largely unidentified.
Purpose of the Study:
- To investigate the role of additional genetic mutations in the development of RET-associated human medullary thyroid carcinoma (MTC) and pheochromocytoma (PC).
- To identify novel genetic alterations that may contribute to tumor progression and varied disease expression in these endocrine neoplasms.
Main Methods:
- Analysis of somatic mutations in the cell cycle regulator P18 (also known as CDKN2C or p18INK4c) within human MTC and PC tumor samples.
- Functional assessment of identified P18 mutations to determine their impact on protein function and stability.
Main Results:
- The study identified somatic mutations in the P18 gene in human RET-associated MTC and PC.
- These mutations were located in the cyclin-dependent kinase-interacting region of P18(INK4C), leading to amino acid substitutions.
- The identified P18 mutations were shown to partially inhibit P18(INK4C) function and reduce its protein stability.
Conclusions:
- P18 acts as a tumor suppressor gene in the context of human MTC and PC development.
- Somatic mutations in P18 represent a significant additional genetic event in RET-associated MTC and PC, contributing to tumorigenesis.
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